Skip to main content
placeholder image

AR-12 Inhibits Multiple Chaperones Concomitant With Stimulating Autophagosome Formation Collectively Preventing Virus Replication

Journal Article


Download full-text (Open Access)

Abstract


  • We have recently demonstrated that AR-12 (OSU-03012) reduces the function and ATPase activities of multiple HSP90 and HSP70 family chaperones. Combined knock down of chaperones or AR-12 treatment acted to reduce the expression of virus receptors and essential glucosidase proteins. Combined knock down of chaperones or AR-12 treatment inactivated mTOR and elevated ATG13 S318 phosphorylation concomitant with inducing an endoplasmic reticulum stress response that in an eIF2α—dependent fashion increased Beclin1 and LC3 expression and autophagosome formation. Over-expression of chaperones prevented the reduction in receptor/glucosidase expression, mTOR inactivation, the ER stress response, and autophagosome formation. AR-12 reduced the reproduction of viruses including Mumps, Influenza, Measles, Junín, Rubella, HIV (wild type and protease resistant), and Ebola, an effect replicated by knock down of multiple chaperone proteins. AR-12—stimulated the co-localization of Influenza, EBV and HIV virus proteins with LC3 in autophagosomes and reduced viral protein association with the chaperones HSP90, HSP70, and GRP78. Knock down of Beclin1 suppressed drug-induced autophagosome formation and reduced the anti-viral protection afforded by AR-12. In an animal model of hemorrhagic fever virus, a transient exposure of animals to low doses of AR-12 doubled animal survival from ∼30% to ∼60% and suppressed liver damage as measured by ATL, GGT and LDH release. Thus through inhibition of chaperone protein functions; reducing the production, stability and processing of viral proteins; and stimulating autophagosome formation/viral protein degradation, AR-12 acts as a broad-specificity anti-viral drug in vitro and in vivo. We argue future patient studies with AR-12 are warranted.

Authors


  •   Booth, Laurence (external author)
  •   Roberts, Jane L. (external author)
  •   Ecroyd, Heath
  •   Tritsch, Sarah R. (external author)
  •   Bavari, Sina (external author)
  •   Reid, St. Patrick (external author)
  •   Proniuk, Stefan (external author)
  •   Zukiwski, Alexander (external author)
  •   Jacob, Abraham (external author)
  •   Sepulveda, Claudia S. (external author)

Publication Date


  • 2016

Citation


  • Booth, L., Roberts, J., Ecroyd, H., Tritsch, S., Bavari, S., Reid, S., Proniuk, S., Zukiwski, A., Jacob, A., Sepulveda, C. et al (2016). AR-12 Inhibits Multiple Chaperones Concomitant With Stimulating Autophagosome Formation Collectively Preventing Virus Replication. Journal of Cellular Physiology, 231 (10), 2286-2302.

Scopus Eid


  • 2-s2.0-84975074244

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2092&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/1066

Number Of Pages


  • 16

Start Page


  • 2286

End Page


  • 2302

Volume


  • 231

Issue


  • 10

Abstract


  • We have recently demonstrated that AR-12 (OSU-03012) reduces the function and ATPase activities of multiple HSP90 and HSP70 family chaperones. Combined knock down of chaperones or AR-12 treatment acted to reduce the expression of virus receptors and essential glucosidase proteins. Combined knock down of chaperones or AR-12 treatment inactivated mTOR and elevated ATG13 S318 phosphorylation concomitant with inducing an endoplasmic reticulum stress response that in an eIF2α—dependent fashion increased Beclin1 and LC3 expression and autophagosome formation. Over-expression of chaperones prevented the reduction in receptor/glucosidase expression, mTOR inactivation, the ER stress response, and autophagosome formation. AR-12 reduced the reproduction of viruses including Mumps, Influenza, Measles, Junín, Rubella, HIV (wild type and protease resistant), and Ebola, an effect replicated by knock down of multiple chaperone proteins. AR-12—stimulated the co-localization of Influenza, EBV and HIV virus proteins with LC3 in autophagosomes and reduced viral protein association with the chaperones HSP90, HSP70, and GRP78. Knock down of Beclin1 suppressed drug-induced autophagosome formation and reduced the anti-viral protection afforded by AR-12. In an animal model of hemorrhagic fever virus, a transient exposure of animals to low doses of AR-12 doubled animal survival from ∼30% to ∼60% and suppressed liver damage as measured by ATL, GGT and LDH release. Thus through inhibition of chaperone protein functions; reducing the production, stability and processing of viral proteins; and stimulating autophagosome formation/viral protein degradation, AR-12 acts as a broad-specificity anti-viral drug in vitro and in vivo. We argue future patient studies with AR-12 are warranted.

Authors


  •   Booth, Laurence (external author)
  •   Roberts, Jane L. (external author)
  •   Ecroyd, Heath
  •   Tritsch, Sarah R. (external author)
  •   Bavari, Sina (external author)
  •   Reid, St. Patrick (external author)
  •   Proniuk, Stefan (external author)
  •   Zukiwski, Alexander (external author)
  •   Jacob, Abraham (external author)
  •   Sepulveda, Claudia S. (external author)

Publication Date


  • 2016

Citation


  • Booth, L., Roberts, J., Ecroyd, H., Tritsch, S., Bavari, S., Reid, S., Proniuk, S., Zukiwski, A., Jacob, A., Sepulveda, C. et al (2016). AR-12 Inhibits Multiple Chaperones Concomitant With Stimulating Autophagosome Formation Collectively Preventing Virus Replication. Journal of Cellular Physiology, 231 (10), 2286-2302.

Scopus Eid


  • 2-s2.0-84975074244

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2092&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/1066

Number Of Pages


  • 16

Start Page


  • 2286

End Page


  • 2302

Volume


  • 231

Issue


  • 10